The Innocent- Looking Seeds of Metastasis

Scientist Michel Haffner, M.D., who studies prostate cancer, is a molecular archeologist. Digging with precision and delicacy, he uncovers layer after layer – creating a timeline of what’s happening in individual bits of tumor, so that he can capture the true story of what went wrong. "In many men, multiple, independent tumor nodules can be identified within a diseased prostate gland," says Haffner. Although just millimeters away from each other inside the same gland, "these individual lesions in the prostate are often genetically different. They also have different structures, and they can contribute to the progression of the disease in different ways."

"How are tumors within the
prostate related to distant, lifethreatening
metastases?"

Why aren’t all these little tumors alike? And how are tumors within the prostate related to distant, life-threatening metastases? Haffner is part of a multidisciplinary team working to find out. The team, including Angelo De Marzo, M.D., Ph.D., William Isaacs, Ph.D., William Nelson, M.D., Ph.D., and Srinivasan Yegnasubramanian, M.D., Ph.D., "has started to address the question of genealogy of aggressive prostate cancer in a unique way," says Haffner. Thanks to one patient who agreed to donate tissue at an autopsy that was performed shortly after his death, the team received tissue samples from the primary prostate tumor and also from distant metastases. "We used comprehensive whole-genome sequencing to determine the blueprint of all cancer-associated alterations in the metastases," looking to see which genes were involved, and how they related to the cancer that was found within the prostate gland. When they compared the genetic makeup of the metastatic cells with that of the cancer cells confined to the prostate, "to our great surprise, we found that only a very small and well-differentiated lesion in the primary tumor showed the same set of mutations that were also found in the metastases," says Haffner. "The vast majority of other lesions appeared not to be strongly related to the metastases. This suggests that a small, microscopic lesion in the primary tumor can generate the entire metastatic burden."

It is troubling to think that one innocentlooking bit of tumor in the prostate – welldifferentiated, like the "good" cancers that earn a low Gleason score – could contain the seeds for all the trouble that comes when cancer spreads to distant sites. "This finding highlights the complexity and heterogeneity of prostate cancers," says Haffner, "and stresses the need for new molecular markers that will allow us to determine early on if a lesion shows a high risk for metastasis."